beta-cyano steroidal compounds



United States Patent 3,330,851 fl-CYANO STERGIDAL COMPOUNDS Seymour D. Levine, Princeton, and Patrick A. Diassi,

Westfield, N.J., assignors, by mesne assignments, to

E. R. Squibb & Sons, Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Mar. 16, 1965, Ser. No. 440,311

5 Claims. (Cl. 260-464) This invention relates to new steroidal compounds and, more particularly, to new steroids of the A-norandrostane series, new intermediates useful in the preparation of the same, and processes for preparing the same.

The new final products of this invention are of the Formula I:

wherein Y is [SI-hydrogen or B-cyano; R is hydroxy or acyloxy; and R is vinyl, ethynyl, halo substituted vinyl, trifluorornethyl substituted vinyl, halo substituted ethynyl and trifluoromethyl substituted ethynyl. Among the suit able acyloxys may be mentioned the acyloxy radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e. g., acetic, propionic, butyric, hexanoic and enanthic acid), the lower alkenoic acids, the cycloalkane carboxylic acids, the cycloalkene carboxylic acids, the monocyclic aromatic carboxylic acids (e. g., benzoic acid), and the monocyclic aryl(lower alkanoic) acids (e.g., phenacetic and ,B-phenylpropionic acid). Among the suitable halogen substituted 'vinyls may be mentioned perhalovinyls, such as trifiuorovinyl, trichlorovinyl, 1,2-difluoro-2-chlorovinyl and 1,2- difiuoro-Z-brornovinyl; the dihalovinyls, such as 1,2-difluorovinyl, 2,2-difiuorovinyl, l-chloro-Z-fluorovinyl, lbromo-Z-fiuorovinyl, and 1,2-dichlorovinyl; and the monohalovinyls, such as l-fluorovinyl, 2-fluor0vinyl, l-chlorovinyl, 2-chlorovinyl, and 1-bromovinyl. Among the suitable halogen substituted ethynyls may be mentioned fluoroethynyl, chloroethynyl and bromoethynyl.

The final products of this invention are physiologically active compounds that possess fertility inhibiting activity. Hence, they may be administered orally or parenterally in lieu of known anti-fertility agents, such as progestagens and estrogens for control of conception, the dose being adjusted for the activity of the particular compound.

The compounds of this invention are prepared by interacting a compound of the Formula II:

wherein Y is as hereinbefore defined and R" is keto or ketal, with a compound of the formula: R'X, wherein R is as hereinbefore defined, and X is an activating group such as magnesium bromide, lithium or a complex thereof (e. g., a lithium ethylenediamine complex). When Y is cyano, a Z-ketal (R is ketal) must be used. When Y is 3,33%,851 Patented July 11, 1967 hydrogen, either a 2-ketal or 2-ketone may be used as the reactant. Although any ketal may be used, the preferred ketals are those with alkanediols, such as ethylene glycol and propylene glycol. To complete the reaction, water is then added, thereby yielding products of the Formula III wherein Y, R and R" are as herein-before defined.

If the compound of Formula III formed contains a 2- ketal group, it may be hydrolyzed, by treatment with an aqueous solution of a strong acid, such as p-toluenesultonic acid, to yield the corresponding 2-keto derivative. if a l7-ester is desired as the final product, the compound of Formula III, in its free 2-keto form, is reacted with the acyl chloride or acid anhydride of the desired acid, preferably one of the acids mentioned hereinbefore, to yield the 17-ester.

In those instances where ketals of Formula II are used, they may be prepared by first treating either SB-cyano-A- nortestosterone (prepared as described in U. S. patent application, Serial No. 355,913, filed March 30, 1964,- now U. S. Patent 3,271,437) or S/B-A-norandrostane-Z-onel7B-ol with a ketalizing agent, such as ethylene glycol or propylene glycol, in the presence of a strong acid, such as p-toluenesulfonic acid, to yield the corresponding Z-ketal Example 1 .1 7a-ethynyl-5fl-cyan0-A-n0randr0stane- 2-0ne-17/3-0l-2-ethylene ketal (a) Preparation of 5,8- cyano-A-n0randrostane-2-one- 17,8-01 Z-ethylene ketal 17-acetate.-A mixture of 115 mg. of 5,8-cyano-A-nortestosterone and 7 mg. of p-toluenesulfonic acid is stirred and refluxed in 40 m1. of benzene and 3 ml. of ethylene glycol for one day and the water removed by a calcium carbide trap. The reaction mixture is diluted with water and the benzene layer is separated. The aqueous layer is extracted with additional benzene. The combined benzene extracts are washed with 8% salt solution and evaporated to give a residue which is acetylated by refluxing in 2 ml. of acetic anhydride containing 0.2 ml. of pyridine for one hour. The reaction mixture is poured into ice-water and extracted with chloroform. The chloroform extracts are washed with a saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated to dryness. Plate chromatography of the residue on neutral alumina (Activity V) using a mixture of chloroform and hexane (1:2) as the developing solvent gives a major band at about Rf 0.35 which is detectable with iodine. Elution with ethyl acetate, evaporation, and crystallization of the residue from isopropyl ether-hexane gives about mg. of SB-cyano-A-norandrostane-2-one-l7B-ol Z-ethylene ketal 17-acetate, M.P. about 175177. The analytical sample is prepared by recrystallization from isopropyl ether-hexane, M.P. about 182.5- 183.5; +3 (EtOH); 7t KBr 4.50 and 5.77m 1 Si(CH 9.20 (s., 18Me), 8.78 (s., 19-Me), 7.97 (s., 17,8-01 Z-ethylene ketal.(i) A solution of mg. of 5,3-

Analysis.-Calcd for C H O N (387.50): C, 71.29; H, 8.58; N, 3.61. Found: C, 71.28; H, 8.59; N, 3.50.

(b) Preparation of 55 cyano-A-norandrostane-2-0ne- 175-01 Z-ethylene ketaL-(i) A solution of 100 mg. of B- cyano-A-norandrostane-2-one-17,8-01 2-ethylene ketal l7- acetate in 1 ml. of aqueous potassium carbonate solution and 10 ml. of methanol is stirred at room temperature for 18.5 hours. The reaction mixture is diluted with water and extracted with chloroform. The chloroform extracts are washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness. Plate chromatography of the residue on neutral alumina (Activity V) using a mixture of chloroform and hexane (2:1) as the developing solvent gives a major band which is detectable with iodine. Elution with ethyl acetate, evaporation, and crystallization of the residue from isopropyl ether gives about 40 mg. of SB-cyano-A-norandrostane-Z- one-l7p-ol 2-ethylene ketal, M.P. about 172-174". The analytical sample is prepared by recrystallization from isopropyl ether, M.P. about 1755-1765, +6 (EtOH); KBr 2.85 and 450 'r Si(CH 9.26 (s., l8-Me), 8.79 (s., 19Me), 6.12 (m., ketal methylene) and 6.38 (m., 17H).

Analysis.Calcd for C H O N (345.47): C, 73.00; H, 9.05. Found: C, 72.92; H, 9.01.

(ii) Ketalization of 5 3-cyano-A-nortestosterone as described in Step (i) of this example gives rise to SB-cyano- A-norandrostane-Z-one-17 3-01 2-ethylene ketal.

(0) Preparation of 5,8 cyano-A-n0randr0stane 2,17- dione-Z-ethylene ketaL-A solution of 50 mg. of 513- cyano-A-norandrostane-2-one-17,8-01 2-ethylene ketal in 2 ml. of acetone is treated dropwise with stirring with an equivalent amount of chromium trioxide-sulfuric acid. The reaction mixture is treated with one drop of pyridine, filtered and diluted with water. The aqueous phase is extracted with ether. The ether extracts are Washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness. Crystallization of the residue from 'chloroform-isopropyl ether gives about 27 mg. of 5,8-

cyano-A-norandrostane-2,17-dione 2-ethylene ketal, M.P. about 2l2.5213.5. The analytical sample is prepared by recrystallization from chloroform-isopropyl ether, M.P. about 2135-2145", +73 (EtOH); )t KBr 4.50 and 5.78p; 1- Si(CH 9.12 (s., 18-Me), 8.76 (s., 19-Me) and 6.13 (m., ketal methylene).

Analysis.Calcd for C H O N (343.45): C, 73.43; H, 8.51; N, 4.08. Found: C, 73.40; H, 8.52; N, 4.32.

(d) Preparation 0 17a-ethynyl-5fi-cyan0-A-n0randr0- stane-Z-one-Ufi-ol Z-ethylene ketal.A mixture of 200 mg. of 5,8-cyano-A-norandrostane-2,17-dione 2-ethylene ketal and 100 mg. of lithium acetylide ethylene-diamine complex in 10 ml. of benzene and 10 ml. of tetrahydrofuran under an atmosphere of helium is slowly warmed to 45 over a one hour period and maintained at this temperature for 6 additional hours. The reaction mixture is treated with 5 ml. of water and refluxed for one hour, diluted with water and extracted with chloroform. The chloroform extracts are washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness.

Crystallization of the residue from methanol gives 61 mg.

of l7a-ethynyl-5fl-cyano-A-norandrostane-2-one-175-01 2- ethylene ketal, M.P. about 262-264. The analytical sample is prepared by recrystallization from methanolisopropyl ether, M.P. about 269270, 32 (EtOH 1 drop pyridine); x KBr 2.92, 3.08 and 4.50,LL.

Analysis.--Calcd for C H O N (369.49): C, 74.76; H, 8.46. Found: C, 74.65; H, 8.57.

Example 2.1 7 a-ethynyl-S fl-cyano-A -n0ranarostane- 2-on e-1 75-01 A mixture of 220 mg. of 17a-ethynyl-5B-cyano-A-nor androstane-2-one-l7fl-ol 2-ethylene ketal and 25 mg. of p-toluene-sulfonic acid in 2 ml. of water and ml. of acetone is refluxed for 22 hours, diluted with water and the acetone evaporated. The aqueous phase is extracted with chloroform. The chloroform extracts are washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness. Plate chromatography of the residue on neutral alumina (Activity V) using chloroform as the developing solvent gives a major band which is detectable with iodine. Elution with ethyl acetate, evaporation, and crystallization of the residue from ethyl acetate-isopropyl ether gives 112 mg. of 17a-ethynyI-SB-cyano-A-norandrostane-2-one-l7fl-ol, M.P. about 174-176. The analytical sample is prepared by recrystallization from ethylacetatepetroleum ether (B.P. 3075), M.P. about l8l.5-l82.5, [M l24 (EtOH); 'Y KBr 2.93, 3.05, 4.50 and 5.72% T Si(CH 9.13 (s., 19-Me), 8.61 (s., 19-Me), and 7.42 (s., l7a-ethynyl-H).

Analysis.-Calcd for C21H27O2N (325.43): C, 77.50; H, 8.36. Found: C, 77.59; H, 8.42.

Exam pl e 3 .1 7 -ot-ethynyl-5 fi-cyano-A -n0randrostane- 2-0ne-17p-0l acetate A solution of 0.0033 ml. of perchloric acid in 0.3 ml. of acetic anhydride is added to 500 mg. of 17a-ethynyl-5flcyano-A-norandrostane-2-one-175-01 in 10 ml. of acetic anhydride. The reaction mixture is stirred at room temperature for 30 minutes and then poured into ice-water and extracted with chloroform. The chloroform extracts are washed with a saturated sodium bicarbonate solution, 8% salt solution, dried over sodium sulfate and evaporated to dryness to give 17a-ethynyI-SB-cyano-A-norandrostane-2-one-l7fi-ol acetate.

Similarly, by substituting any other acyl chloride or acid anhydride for the acetic anhydride in the procedure of Example 3, the corresponding l7-ester is formed. Thus, propionic anhydride and benzoyl chloride yield the propionate and benzoate, respectively.

Example 4.17a-trifluoropropynyl-Sfl-cyano-A-n0randr0stane-2-0ne-17 3-0l Z-ethylene ketal A solution of mg. of 5,8-cyano-A-norandrostane-Z, 17-dione 2-ethylene ketal in 15 ml. of tetrahydrofuran is treated with an excess of trifluoropropynylmagnesium bromide (prepared from ethyl magnesium bromide and excess trifluoropropyne in tetrahydrofuran solution). The reaction mixture is refluxed for 6 hours, cooled, and then treated with a saturated ammonium chloride solution and the organic layer separated. The aqueous layer is extracted with chloroform. The combined organic fractions are washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness to give 17a-trifluoropropynyl-SB-cyano-A-norandrostane-2-one-1718- o1 2-ethylene ketal.

Example 5 .--1 7 a-and 17,3-chloroethynyl-Sfi-cyano-A- n0randrostane-2-0ne-17-0ls Z-ethylene ketal A solution of 250 mg. of SB-cyano-A-norandrostame-2, 17-dione 2-ethylene ketal in 20 ml. of ether is added dropwise to an excess of chloroethynyllithium (prepared from cis-1,2-dichloroethylene and methyllithium in ether) solution over a 10 minute period. The reaction mixture is left at room temperature for 2.5 hours and treated with icewater and additional ether. The ether layer is separated, washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness to give a mixture of 17aand 17j8-chloroethynyl-5fi-cyano A norandrostane-2-one-l7- ols 2-ethylene ketal which are separable by chromatography on neutral alumina (Activity V).

Example 6.17a-trifluorovinyl-Sfi-cyano-A-norandrostane-Z-one-I 7 fl-ol Z-ethylene ketal A solution of 300 mg. of Sfi-cyano-A-norandrostane-2, l7-dione Z-ethylene ketal in 25 ml. of tetrahydrofuran is treated with an excess of trifluorovinylmagnesium bromide (prepared from magnesium and trifluorobromoethylene in tetrahydrofuran solution). The reaction mixture is refluxed for 6 hours, cooled, and then treated with a saturated ammonium chloride solution and the organic layer separated. The aqueous layer is extracted with chloroform. The combined organic fractions are washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness to give 17e-trifluorovinyl-55-cyano-A- norandrostane-Z-one-l75-01 2-ethylene ketal.

Similarly, by substituting the indicated magnesium bromide :for the trifiuorovinylmagnesium bromide in the procedure of Example 6, the indicated 17a-R'-5B-cyano-A- norandrostane-Z-one-l718-01 Z-ethylene ketal is formed:

Example Reactant Product R is Viuylmagnesium bromide fi-Chlorovinyhuagnesium bromide... a,fl-Dichlorovinylrnagensium bromide.

a,fi-Difluoroviny1magnesium bromide- Following the procedure of Example 2, but substituting 17a-trifluoropropynyl-SB-cyano-A-norandrostane-Z one 17B-ol Z-ethylene ketal for the l7u-ethyny1-5/3-cyano-A- norandrostane-Z-one-l7 3-01 2-ethylene ketal, 17a-trifluoropropynyl-Sfl-cyano-A-norandrostane 2 one 175 01 is formed.

Similarly, by substituting the following R-5;8-cyano-A- norandrostane-Z-one-l73-01 2-ethylene ketals for the 170:- ethynyl-5 3-cyanoA-norandrostane-2-one-175-01 2 ethylene ketal in the procedure of Example 2, the indicated R'- Sfl-cyano-A-norandrostane-Z-one-175-01 is formed.

Example Reactant R is Product R is Example 18.] 7a-triflu0ropr0pynyl-SB-cyano-A- norandrosnme-Z -ne-1 7 {3-01 A cetate Following the procedure of Example 3, but substituting an equivalent amount of l7a-trifiuoropropynyl-Sfi-cyano- A-norandrostane-Z-one-1719-01 for the l7a-ethynyl-5/3- cyano A norandrostane-Z-one-1718-01 (there is obtained 17a-trifiuoropropynyl-SB-cyano-A-norandrostane-Z one 17,301 acetate.

Example 19.17a-etltynyl-5,B-A-n0randr0stane-2-0nel 7 ,Q-ol

Following the procedure in Example 1, Step (d), but substituting 3-A-norandrostane-2,17-dione =for S S-cyano- A-norandrostane-2,l7-dione Z-ethylene ketal, there is obtained 17a-ethynyl-Sfi-A-norandrostane-2-one 17/3 01, A KBr 2.91, 3.03 and 5.78a.

stane-2-0ne-17 3-0l Following the procedure in Example 4, but substituting 5fiA-norandrostane-2,17-dione for 5 3-cyano-A-norandrostane-2,17-dione 2-ethylene ketal, there i obtained 17atrifiuoropropynyl-Sfl-A-norandrostane-2-one-17,8-01.

Example Z].]7aand 17/8-chl0roethynyl-5fi-A- norandrostan e-2-0n e-1 7 -0ls Following the procedure in Example 5, but substituting SB-A-norandrostane-Z,17-dione for SB-cyano-A-norandrostane-2,17-dione 2-ethylene ketal, there is obtained a mixture of 17w and 17,8-chloroethynyl-S/i-A-norandrostane- 2-one-l7-o1s.

Following the procedure in Example 6, but substituting 5fl-A-n0randrostane-2,17-dione for 5/i-cyan0-A-norandro stane-2,17-dione Z-ethylene ketal, there is obtained 17atrifluorovinyl-Sfl-A-norandrostane-Z-one-17,8-01.

Hydrogenation of 17a-trifluoropropynyl-5B-A noran drostane-2-one-l7fi-ol at 45 p.s.i. with Lindlar catalyst gives 17a-trifluoropropenyl-Sfi-A-norandrostane-Z-one.

Example 24.] 7a-ethynyl-5f3-A -n0randrostane-2-0ne- 17,6-0l acetate Following the procedure of Example 3, but substituting 17a-ethynyl-5B-A-norandrostane-Z-one-1713-01 for the 17aethynyl-Sfl-cyano-A-norandrostane-2-one-17/3 01, there is obtained 17a-ethynyI-SB-A-norandrostane-Z-one 17/3 01 acetate.

Similarly, the 17-free alcohol of Examples 20 through 23 can be converted to their acetate derivatives.

The invention may be otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound of the formula References Cited UNITED STATES PATENTS 3,271,437 9/1966 Levine 260-464 CHARLES B. PARKER, Primary Examiner. I OSEPH P. BRUST, Examiner. 

1. A COMPOUND OF THE FORMULA 